Olczak Kaya J, Taylor-Bateman Victoria, Nicholls Hannah L, Traylor Matthew, Cabrera Claudia P, Munroe Patricia B
Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
J Intern Med. 2021 Dec;290(6):1130-1152. doi: 10.1111/joim.13352. Epub 2021 Jul 8.
Essential hypertension is a complex trait where the underlying aetiology is not completely understood. Left untreated it increases the risk of severe health complications including cardiovascular and renal disease. It is almost 15 years since the first genome-wide association study for hypertension, and after a slow start there are now over 1000 blood pressure (BP) loci explaining ∼6% of the single nucleotide polymorphism-based heritability. Success in discovery of hypertension genes has provided new pathological insights and drug discovery opportunities and translated to the development of BP genetic risk scores (GRSs), facilitating population disease risk stratification. Comparing highest and lowest risk groups shows differences of 12.9 mm Hg in systolic-BP with significant differences in risk of hypertension, stroke, cardiovascular disease and myocardial infarction. GRSs are also being trialled in antihypertensive drug responses. Drug targets identified include NPR1, for which an agonist drug is currently in clinical trials. Identification of variants at the PHACTR1 locus provided insights into regulation of EDN1 in the endothelin pathway, which is aiding the development of endothelin receptor EDNRA antagonists. Drug re-purposing opportunities, including SLC5A1 and canagliflozin (a type-2 diabetes drug), are also being identified. In this review, we present key studies from the past, highlight current avenues of research and look to the future focusing on gene discovery, epigenetics, gene-environment interactions, GRSs and drug discovery. We evaluate limitations affecting BP genetics, including ancestry bias and discuss streamlining of drug target discovery and applications for treating and preventing hypertension, which will contribute to tailored precision medicine for patients.
原发性高血压是一种复杂的性状，其潜在病因尚未完全明确。若不加以治疗，会增加包括心血管疾病和肾脏疾病在内的严重健康并发症的风险。自首次针对高血压的全基因组关联研究开展至今已近15年，在经历了缓慢的起步阶段后，现在已有超过1000个血压（BP）位点，可解释约6%的基于单核苷酸多态性的遗传力。高血压基因发现方面的成功提供了新的病理学见解和药物发现机会，并转化为血压遗传风险评分（GRSs）的开发，有助于对人群疾病风险进行分层。比较最高和最低风险组发现，收缩压相差12.9毫米汞柱，高血压、中风、心血管疾病和心肌梗死风险存在显著差异。GRSs也正在抗高血压药物反应中进行试验。已确定的药物靶点包括NPR1，目前一种激动剂药物正在进行临床试验。在PHACTR1基因座上鉴定出的变异为内皮素途径中EDN1的调控提供了见解，这有助于内皮素受体EDNRA拮抗剂的开发。还在确定包括SLC5A1和卡格列净（一种2型糖尿病药物）在内的药物重新利用机会。在本综述中，我们介绍过去的关键研究，突出当前的研究途径，并展望未来，重点关注基因发现、表观遗传学、基因-环境相互作用、GRSs和药物发现。我们评估影响血压遗传学的局限性，包括血统偏差，并讨论简化药物靶点发现以及治疗和预防高血压的应用，这将有助于为患者提供量身定制的精准医学。
